Heterocyclic amidino substituted ureas and their pharmaceutical uses

ABSTRACT

This invention relates to methods for the prophylactic and curative treatment of gastrointestinal and cardiovascular disorders and parasitic infections in humans and animals, using a class of hetrocyclic amidino substituted urea and thiourea compounds, a novel class of heterocyclic amidino substituted urea and thiourea compounds and pharmaceutical compositions and animal feed additives including the same.

FIELD OF THE INVENTION

This invention relates to a novel class of heterocyclic amidinosubstituted ureas and thioureas and their pharmaceutical use in methodsfor producing gastrointestinal, cardiovascular, and antiparasiticaction, among others.

REPORTED DEVELOPMENTS

Phenylamidinoureas and their uses as antisecretory, antispasmodic,anti-ulcerogenic, anesthetic and antidiarrheal agents have been reportedin Arzneimittel Forschung (Drug Research) 28 (II), 1433-1480 (1978), andU.S. Pat. Nos. 4,025,652, 4,058,557, 4,060,635, 4,088,785, 4,115,564,4,115,647, 4,117,165, 4,147,804, 4,150,154, 4,169,155, 4,178,387,4,204,000 and 4,220,658.

This invention relates to a class of heterocyclic amidino substitutedurea and thiourea compounds which also possess valuable pharmaceuticalproperties.

SUMMARY OF THE INVENTION

This invention relates to the treatment of humans and animals afflictedwith gastrointestinal disorders, spasmolytic disorders, ulcergenicdisorders, cardiovascular disorders, diarrheal disorders, and parasiticinfestations with compositions containing an effective amount ofheterocylic amidino substituted urea or thiourea according to Formula I##STR1## where: X is O or S;

n is 0 to 3;

R₁ is a 5 to 7 atom ring or a 7 to 13 atom fused or bridged ring whichmay include 1 to 4 hetero atoms of N, O or S; and containing a total ofabout 3 to about 20 carbon atoms; and the N- or S-oxides thereof;

R₂, R₃ and R₄ are hydrogen or lower alkyl;

R₅ and R₆ are hydrogen, alkyl, cycloalkyl, aralkyl, aryl, alkenyl,alkoxy or a heterocyclic group, or R₅ and R₆ together with the nitrogensto which they are attached form a 3 to 7 atom ring which may include 0to 2 additional hetero atoms of N, O or S; and the nontoxic acidaddition salts thereof.

DETAILED DESCRIPTION OF THE INVENTION

This invention also relates to novel compounds which are useful in thesemethods and include those according to Formula I where:

n is 0, 1, 2 or 3;

R₁ is a substituted or unsubstituted 5, 6 or 7 atom ring including 1 to3 hetero atoms of N, O or S; and N- and S-oxides thereof;

R₂ is hydrogen or lower alkyl;

R₃ and R₄ are hydrogen;

R₅ and R₆ are hydrogen, lower alkyl, lower alkenyl, cycloalkyl, loweralkoxy, or aralkyl or R₅ and R₆ together with the nitrogen to which theyare attached form a 3 to 7 atom heterocycle.

This invention further relates to a novel class of compounds accordingto Formula I, which are useful in the above methods, in which R₁ is oneof the following heterocylic groups: 1-pyrrole, 2-pyrrole, 3-pyrrole,2-furan, 3-furan, 2-thiophene, 3-thiophene, 2-tetrahydrothiophene,3-tetrahydrothiophene, 2-imidazole, 2-imidazole, 4-imidazole,5-imidazole, 2-oxazole, 4-oxazole, 2-thiazole, 4-thiazole, 5-thiazole,1-pyrazole, 3-pyrazole, 4-pyrazole, 5-pyrazole, 1-pyrrolidine,2-pyrrolidine, 3-pyrrolidine, 1-(3-pyrroline), 2-(3-pyrroline),3-(3-pyrroline), 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidine,4-pyrimidine, 5-pyrimidine, 6-pyrimidine, 2-purine, 6-purine, 8-purine,9-purine, 2-quinoline, 3-quinoline, 4-quinoline, 5-quinoline,6-quinoline, 7-quinoline, 8-quinoline, 1-isoquinoline, 3-isoquinoline,4-isoquinoline, 5-isoquinoline, 6-isoquinoline, 7-isoquinoline,8-isoquinoline, or carbazole.

The heterocylic groups above may be mono-, di-, tri- ortetra-substituted by ring substituents, such as, halogen, lower alkyl,lower alkenyl, aryl, lower alkynyl, aralkyl, nitro, cyano, sulfonyl,hydroxyl, carboxyl, lower alkanoyl, lower alkoxy, aryl lower alkoxy,halo lower alkoxy, amido, amino, lower alkyl acyloxy, alkylamino, loweralkoxyamino, and aralkoxyamino.

A preferred embodiment of this invention is a compound according toFormulae II-IV ##STR2## m is zero to four; n is zero, one, two or three;

R represents a ring substituent as described above, and the N-oxides ofthe pyridyl nitrogen atom; and

R₂, R₅ and R₆ are as described in Formula I above.

Another preferred embodiment of this invention is a compound accordingto Formula V or VI ##STR3## where: m is zero to three

n is zero, one, two or three;

R represents a ring substituent as described above; and the S-oxides ofthe thiophene sulfur atoms, such as, thiophenylsulfoxide and thiophenylsulfone;

R₂, R₅ and R₆ are as defined above in Formula I;

and the nontoxic acid addition salts thereof.

A particularly preferred embodiment of this invention is a compoundaccording to Formula II, III, IV, V and VI, wherein X, m, n, R, and R₂are as described above, and one of R₅ and R₆ are phenyl or substitutedphenyl. The most preferred substituted phenyl groups are those which areortho- and diortho-substituted.

In any discussion of the true structure of an amidinourea, tautomerismmust be considered. It should be clear to anyone skilled in the art thatthe amidinourea chain can be legitimately represented in any one ofseveral tautomeric forms. When the amidinourea is in solution, one formmay predominate over another depending upon the degree and location ofsubstitution and on the nature of the solvent. The rates of conversionof one tautomer to another will depend upon the nature of the solvent,the degree of hydrogen bonding permitted, the temperature, and possiblyother factors (such as pH, trace impurities and the like).

To illustrate what is meant by this, a number of likely structures arehere shown for just one of the compounds of this invention: ##STR4##

Of course, other structures are possible, such as those with hydrogenbonding. ##STR5##

Furthermore, the heterocylic atom may contribute to structuresreflecting hydrogen bonding. ##STR6##

As employed above and throughout the disclosure, the following terms,unless otherwise indicated, shall be understood to have the followingmeanings:

"Alkyl" means a saturated aliphatic hydrocarbon which may be eitherstraight- or branched-chain. Preferred groups have no more than about 12carbon atoms and may be methyl, ethyl and structural isomers of propyl,butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl and dodecyl.

"Lower alkyl" means an alkyl group as above, having 1 to 6 carbon atoms.Suitable lower alkyl groups are methyl, ethyl, n-propyl, isopropyl,butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl and neopentyl.

"Cycloalkyl" means an aliphatic monocyclic saturated carbocyclic grouphaving 3 to 6 carbon atoms. Preferred groups are cyclopropyl,cyclopentyl and cyclohexyl.

"Alkenyl" means an unsaturated aliphatic hydrocarbon. Preferred groupshave no more than about 12 carbon atoms and 1 to 3 carbon double bondsand may include straight or branched chains, and may be any structuraland geometric isomers of ethenyl, propylenyl, butenyl, pentenyl,hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, and dodecenylor butadienyl, pentadienyl etc. Also included are the cycloalkylenegroups such as cyclopropenyl, cyclopentenyl, cyclohexenyl, etc. and thecycloalkylalkylene groups such as cyclo-propyleneylmethyl, andcyclohexenylmethyl and the like.

"Lower alkenyl" means alkenyl or 2 to 6 carbon atoms such ethylene,propylene, butylene, isobutylene, etc., including all structural andgeometrical isomers thereof.

"Alkynyl" means an unsaturated aliphatic hydrocarbon. Preferred groupshave no more than about 12 carbon atoms and contain one or more triplebonds, including any structural or geometric isomers or acetylenyl,propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl,decynyl, undecynyl, dodecynyl, etc.

"Lower alkynyl" means alkynyl of 2 to 6 carbon atoms such as structuraland geometric isomers of propargyl, butynyl, pentynyl, etc.

"Aryl" means phenyl and substituted phenyl.

"Substituted phenyl" means a phenyl group in which one or more of thehydrogens has been replaced by the same or different substituentsincluding halo, lower alkyl, halo-lower alkyl, nitro, amino, acylamino,hydroxyl, lower alkoxy, aryl lower alkoxy, acyloxy, cyano, halo-loweralkoxy or lower alkyl sulfonyl. The preferred substituted phenyl groupis phenyl in which the 2 and 6 positions are substituted.

"Aralkyl" means an alkyl (preferably a lower alkyl) in which one or morehydrogens is substituted by an aryl moiety (preferably phenyl orsubstituted phenyl), e.g., benzyl, phenethyl, etc.

"Heterocyclic group" or "heterocycle" means a 3, 5, 6 or 7 membered ringhaving 1 to 3 hetero atoms which may be nitrogen, oxygen or sulfur,including pyridyl, pyrimidyl, pyrazolyl, imidazolyl, furyl, thienyl,oxazolyl, thiazolyl, piperidyl, morpholinyl, oxazolidinyl,thiazolidinyl, pyrazolodinyl, imidazolidinyl, piperazinyl,thiamorpholinyl, trimethylenetriaminyl and ethyleneiminyl; where theheterocycle may be mono-, di-, tri- or tetra-substituted by lower alkyl,lower alkenyl, lower alkynyl, aryl, aralkyl, halo, nitro, cyano,sulfonyl, hydroxyl, carboxyl, lower alkanoyl, lowercarboalkoxy, loweralkoxy, aryl lower alkoxy, halo lower alkoxy, amido, amino, loweralkylamino, aralkylamino, lower alkoxyamino, and aralkylamino.

"Substituted heterocycle" means a heterocycle in which one or more ofthe hydrogens on the ring carbons have been replaced by substituents asgiven above with respect to substituted phenyl.

The terms "halo" and "halogen" include all four halogens; namely,fluorine, chlorine, bromine and iodine. The halo alkyls, halophenyl andhalo-substituted pyridyl include groups having more than onehalosubstituent which may be the same or different such astrifluoromethyl, 1-chloro-2-bromo-ethyl, chlorophenyl, 4-chloropyridyl,etc.

"Acyloxy" means an organic acid radical of a lower alkanoic acid oraromatic acid such as acetoxy, propionoxy, benzoyloxy, and the like.

"Acyl" means an organic radical of the formula RCO where R is alkyl oraromatic, such as, lower alkanoyl and aroyl. Exemplary acyl groups areacetyl, benzoyl, napthoyl, etc.

"Lower alkanoyl" means the acyl radical of a lower alkanoic acid such asacetyl, propionyl, butyryl, valeryl, stearoyl, and the like.

"Alkoxy" is intended to include hydroxy alkyl groups, preferably loweralkyl groups such as methoxy, ethoxy, n-propoxy, i-propoxy, and thelike.

The preferred "aralkyl" groups are benzyl and phenethyl.

The preferred "halo lower alkyl" group is trifluoromethyl.

The preferred "halo lower alkoxy" group is trifluoromethoxy.

It is well known in the pharmacological arts that nontoxic acid additionsalts of pharmacologically active amine compounds do not differ inactivities from their free base. The salts merely provide a convenientsolubility factor.

The amidinoureas of this invention may be readily converted to theirnontoxic acid addition salts by customary methods in the art. Thenontoxic salts of this invention are formed from the base amidinoureaand an acid which is pharmacologically acceptable in the intendeddosages. Such salts would include those prepared from inorganic acids,organic acids, higher fatty acids, high molecular weight acids, etc.Exemplary acids are hydrochloric acid, hydrobromic acid, sulfuric acid,nitric acid, phosphoric acid, methane sulfonic acid, benzene sulfonicacid, acetic acid, propionic acid, malic acid, succinic acid, glycolicacid, lactic acid, salicylic acid, benzoic acid, nicotinic acid,phthalic acid, stearic acid, oleic acid, abietic acid, etc.

Representative examples of the compounds of this invention are listed inTables I and II.

The nomenclature used in the tables below and which apply to thecompounds of this invention is as follows: ##STR7## It should beunderstood that alternate nomenclature can be used to adequatelydescribe the compounds of this invention, one such system ofnomenclature being based on the quanidine structure, ##STR8## and whichsystem is used in the preparative example section below.

TABLE I

3-(2-pyridylamidino)-1-methylurea

3-(2-pyridylamidino)-1-ethylurea

3-(2-pyridylamidino)-1-propylurea

3-(2-pyridylamidino)-1-i-propylurea

3-(2-pyridylamidino)-1-butylurea

3-(2-pyridylamidino)-1-i-butylurea

3-(2-pyridylamidino)-1-pentylurea

3-(2-pyridylamidino)-1-propargylurea

3-(2-pyridylamidino)-1-allylurea

3-(2-pyridylamidino)-1-methoxyethylurea

3-(2-pyridylamidino)-1-benzyloxyethylurea

3-(2-pyridylamidino)-1-phenethoxyethylurea

3-(2-pyridylamidino)-1-(N,N-dimethyl)urea

3-(2-pyridylamidino)-1-(N,N-diethyl)urea

3-(2-pyridylamidino)-1-(N,N-tetramethylene)urea

3-(2-pyridylamidino)-1-(N,N-pentamethylene)urea

3-(2-pyridylamidino)-1-(N,N-hexamethylene)urea

3-(2-[3-methylpyridyl]amidino)-1-methylurea

3-(2-[3-methylpyridyl]amidino)-1-ethylurea

3-(2-[3-methylpyridyl]amidino)-1-propylurea

3-(2-[3-methylpyridyl]amidino)-1-i-propylurea

3-(2-[3-methylpyridyl]amidino)-1-i-butylurea

3-(2-[3-methylpyridyl]amidino)-1-pentylurea

3-(2-[3-methylpyridyl]amidino)-1-allylurea

3-(2-[3-methylpyridyl]amidino)-1-propargylurea

3-(2-[3-methylpyridyl]amidino)-1-cyclopropylurea

3-(2-[3-methylpryidyl]amidino)-1-methoxyethylurea

3-(2-[3-methylpyridyl]amidino)-1-benzyloxyethylurea

3-(2-[3-methylpyridyl]amidino)-1-phenethoxyethylurea

3-(2-[3-methylpyridyl]amidino)-1-benzylurea

3-(2-[3-methylpyridyl]amidino)-1-(N,N-dimethyl)urea

3-(2-[3-methylpyridyl]amidino)-1-(N,N-diethyl)urea

3-(2-[3-methylpyridyl]amidino)-1-(N,N-tetramethylene)urea

3-(2-[3-methylpyridyl]amidino)-1-(N,N-pentamethylene)urea

3-(2-[3-chloropyridyl]amidino)-1-methylurea

3-(2-[3-chloropyridyl]amidino)-1-ethylurea

3-(2-[3-chloropyridyl]amidino)-1-propylurea

3-(2-[3-chloropyridyl]amidino)-1-i-propylurea

3-(2-[3-chloropyridyl]amidino)-1-butylurea

3-(2-[3-chloropyridyl]amidino)-1-i-butylurea

3-(2-[3-chloropyridyl]amidino)-1-t-butylurea

3-(2-[3-chloropyridyl]amidino)-1-pentylurea

3-(2-[3-chloropyridyl]amidino)-1-allylurea

3-(2-[3-chloropyridyl]amidino)-1-propargylurea

3-(2-[3-chloropyridyl]amidino)-1-cyclopropylurea

3-(2-[3-chloropyridyl]amidino)-1-cyclobutylurea

3-(2-[3-chloropyridyl]amidino)-1-(N-[3'-cyclopentenyl])urea

3-(2-[3-chloropyridyl]amidino)-1-cyclopropylmethylurea

3-(2-[3-chloropyridyl]amidino)-1-methoxyethylurea

3-(2-[3-chloropyridyl]amidino)-1-benzyloxyethylurea

3-(2-[3-chloropyridyl]amidino)-1-phenethoxyethylurea

3-(2-[3-chloropyridyl]amidino)-1-benzylurea

3-(2-[3-chloropyridyl]amidino)-1-(N,N-dimethyl)urea

3-(2-[3-chloropyridyl]amidino)-1-(N,N-diethyl)urea

3-(2-[3-chloropyridyl]amidino)-1-(N,N-tetramethylene)urea

3-(2-pyridylamidino)-1-(N,N[3'-methyl-3'-azapentamethylene]urea

3-(2-pyridylamidino)-1-(N,N[3'-oxapentamethylene]urea

3-(3-pyridylamidino)-1-methylurea

3-(3-pyridylamidino)-1-ethylurea

3-(3-pyridylamidino)-1-propylurea

3-(3-pyridylamidino)-1-propylurea

3-(3-pyridylamidino-1-butylurea

3-(3-pyridylamidino)-1-i-butylurea

3-(3-pyridylamidino)-1-t-butylurea

3-(3-pyridylamidino)-1-pentylurea

3-(3-pyridylamidino)-1-allylurea

3-(3-pyridylamidino)-1-propargylurea

3-(3-pyridylamidino)-1-cyclobutylurea

3-(3-pyridylamidino)-1-cyclohexylurea

3-(3-pyridylamidino)-1-benzylurea

3-(3-pyridylamidino)-1-methoxyethylurea

3-(3-pyridylamidino)-1-benzyloxyethylurea

3-(3-pyridylamidino)-1-methoxyethylurea

3-(3-pyridylamidino)-1-benzyloxyethylurea

3-(3-pyridylamidino)-1-phenethoxyethylurea

3-(3-pyridylamidino)-1-(N,N-diethyl)urea

3-(3-pyridylamidino)-1-(N,N-dimethyl)urea

3-(3-pyridylamidino)-1-(N,N-pentamethylene)urea

3-(4-pyridylamidino)-1-methylurea

3-(4-pyridylamidino)-1-ethylurea

3-(4-pyridylamidino)-1-propylurea

3-(4-pyridylamidino)-1-i-propylurea

3-(4-pyridylamidino)-1-butylurea

3-(4-pyridylamidino)-1-t-butylurea

3-(4-pyridylamidino)-1-pentylurea

3-(4-pyridylamidino)-1-hexylurea

3-(4-pyridylamidino)-1-propargylurea

3-(4-pyridylamidino)-1-allylurea

3-(4-pyridylamidino)-1-methoxyethylurea

3-(4-pyridylamidino)-1-benzyloxyethylurea

3-(4-pyridylamidino)-1-phenethoxyethylurea

3-(4-pyridylamidino)-1-(N,N-dimethyl-urea

3-(4-pyridylamidino)-1-(N,N-diethyl)urea

3-(4-pyridylamidino)-1-(N-methyl-N-ethyl)urea

3-(4-pyridylamidino)-1-(N,N-tetramethylene)urea

3-(4-pyridylamidino)-1-(N,N-pentamethylene)urea

3-(4-pyridylamidino)-1-(N,N-hexamethylene)urea

3-(4-[2-ethylpyridyl]amidino)-1-methylurea

3-(4-[2-ethylpyridyl]amidino)-1-ethylurea

3-(4-[2-ethylpyridyl]amidino)-1-propylurea

3-(4-[2-ethylpyridyl]amidino)-1-butylurea

3-(4-[2-ethylpyridyl]amidino)-1-i-butylurea

3-(4-[2-ethylpyridyl]amidino)-1-pentylurea

3-(4-[2-ethylpyridyl]amidino)-1-allylurea

3-(4-[2-ethylpyridyl]amidino)-1-propargylurea

3-(4-[2-ethylpyridyl]amidino)-1-methoxyethylurea

3-(4-[2-ethylpyridyl]amidino)-1-benzyloxyethylurea

3-(4-[2-ethylpyridyl]amidino)-1-(N,N-dimethyl)urea

3-(4-[2-ethylpyridyl]amidino)-1-(N,N-diethyl)urea

3-(4-[2-ethylpyridyl]amidino)-1-(N,N-tetramethylene)urea

3-(4-[2,6-dichloropyridyl]amidino)-1-methylurea

3-(4-[2,6-dimethylpyridyl]amidino)-1-methylurea

3-(4-[2-methyl,6-chloropyridyl]amidino)-1-methylurea

3-(2-thiophenylamidino)-1-methylurea

3-(3-thiophenylamidino)-1-methylurea

3-(2-[5-methylthiophenyl]amidino)-1-methylurea

3-(2-[5-chlorothiophenyl]amidino)-3-methylurea

3-(2-pyridyl-N-oxideamidino)-1-(N,N-dimethyl)urea

3-(2-[3-cyanopyridyl]amidino)-1-methylurea

3-(2-[3-carbomethoxypyridyl]amidino)-1-methylurea

3-(2-[3-carboethoxypyridyl]amidino)-1-methylurea

3-(2-[6-chloropyridyl]amidino)-1-methylurea

3-(2-[6-methylpyridyl]amidino)-1-methylurea

3-(2-[3-ethylpyridyl]amidino)-1-methylurea

3-(3-[2-methylpyridyl]amidino)-1-methylurea

3-(3-[2-ethylpyridyl]amidino)-1-methylurea

3-(3-[2,6-dimethylpyridyl]amidino)-1-methylurea

3-(2-[3-cyanothiophenyl]amidino)-1-methylurea

3-(2-[3-carbomethoxythiophenyl]amidino)-1-methylurea

3-(2-[3-carboethoxythiophenyl]amidino)-1-methylurea

3-(3-[2-methoxypyridyl]amidino)-1-methylurea

3-(3-[2-ethoxypyridyl]amidino)-1-methylurea

3-(3-[2-chloropyridyl]amidino)-1-methylurea

1-(2-furylamidino)urea

1-(3-furylamidino)urea

1-(2-[3-methylfuryl]amidino)urea

3-(2-furylamidino-1-ethylurea

3-(2-furylamidino)-1-propylurea

3-(2-furylamidino)-1-i-propylurea

3-(2-furylamidino)-1-butylurea

3-(2-furylamidino)-1-i-butylurea

3-(2-furylamidino)-1-sec-butylurea

3-(2-furylamidino)-1-t-butylurea

3-(2-furylamidino)-1-pentylurea

3-(2-furylamidino)-1-hexylurea

3-(2-furylamidino)-1-heptylurea

3-(2-furylamidino)-1-cyclopropylurea

3-(2-furylamidino)-1-cyclobutylurea

3-(2-pyridyl-N-oxideamidino)-1-methylurea

3-(2-pyridyl-N-oxideamidino)-1-methylurea

3-(4-pyridyl-N-oxideamidino)-1-methylurea

3-(2-furylamidino)-1-methylurea

3-(3-furylamidino)-1-methylurea

3-(2-tetrahydrofurylamidino)-1-methylurea

3-(3-tetrahydrofurylamidino)-1-methylurea

3-(1-imidazoalamidino)-1-methylurea

3-(2-imidazoalamidino)-1-methylurea

3-(4-imidazoalamidino)-1-methylurea

3-(2-oxazoalamidino)-1-methylurea

3-(4-oxazoalamidino)-1-methylurea

3-(5-oxazoalamidino)-1-methylurea

3-(2-thiazoalamidino)-1-methylurea

3-(4-thiazoalamidino)-1-methylurea

3-(5-thiazoalamidino)-1-methylurea

3-(1-pyrazoalamidino)-1-methylurea

3-(1-[3-pyrrolino]amidino)-1-methylurea

3-(2-pyrrolinoamidino)-1-methylurea

3-(1-morpholinoamidino)-1-methylurea

3-(2-morpholinoamidino)-1-methylurea

3-(2-pyrimidinoamidino)-1-methylurea

3-(4-pyrimidinoamidino)-1-methylurea

3-(2-quinolinoamidino)-1-methylurea

3-(4-quinolinoamidino)-1-methylurea

3-(1-isoquinolinoamidino)-1-methylurea

3-(2-furylamidino)-1-cyclopentylurea

3-(2-furylamidino)-1-cyclohexylurea

3-(2-furylamidino)-1-phenylurea

3-(2-furylamidino)-1-benzylurea

3-(2-furylamidino)-1-phenethylurea

3-(2-furylamidino)-1-(N-methyl-N-benzyl)urea

3-(2-furylamidino)-1-(N,N-dibenzyl)urea

1-(2-tetrahydrofurylamidino)urea

1-(2-[3-methyltetrahydrofuryl]amidino)urea

1-(3-tetrahydrofurylamidino)urea

1-(3-[2-methyltetrahydrofuryl]amidino)urea

1-(1-imidazoalamidino)urea

1-(1-[2-methylimidazoal]amidino)urea

1-(4-imidazoalamidino)urea

1-(4-[1-methylimidazoal]amidino)urea

1-(4-[2-methylimidazoal]amidino)urea

1-(2-imidazoalamidino)urea

1-(2-oxazoalamidino)urea

1-(2-[4-methyloxazoal]amidino)urea

1-(4-oxazoalamidino)urea

1-(4-[2-methyloxazoal]amidino)urea

1-(5-oxazoalamidino)urea

1-(5-[2-methyloxazoal]amidino)urea

1-(4-thiazoalamidino)urea

1-(4-[5-methylthiazoal]amidino)urea

1-(5-thiazoalamidino)urea

1-(5-[4-methylthiazoal]amidino)urea

1-(1-pyrazoalamidino)urea

1-(1-[3-pyrrolino]amidino)urea

1-(2-[3-pyrrolino]amidino)urea

1-(1-[2-methyl-3-pyrrolino]amidino)urea

1-(1-[3-methyl-2-pyrrolino]amidino)urea

1-(1-pyrrolidinoamidino)urea

1-(1-[2-methylpyrrolidino]amidino)urea

1-(2-pyrrolidinoamidino)urea

1-(2-[1-methylpyrrolidino]amidino)urea

1-(1-morpholinoamidino)urea

1-(1-[2-methylmorpholino]amidino)urea

1-(2-morpholinoamidino)urea

1-(2-[1-methylmorpholino]amidino)urea

1-(2-[3-methylmorpholino]amidino)urea

1-(1-[3-methylmorpholino]amidino)urea

1-(3-morpholinoamidino)urea

1-(3-[1-methylmorpholino]amidino)urea

1-(3-[2-methylmorpholino]amidino)urea

1-(2-pyrimidinoamidino)urea

1-(2-[4-methylpryimidino]amidino)urea

1-(4-pyrimidinoamidino)urea

1-(4-[2-methylpyrimidino]amidino)urea

1-(2-quinolinoamidino)urea

1-(2-[3-methylquinolino]amidino)urea

1-(4-quinolinoamidino)urea

1-(4-[2-methylquinolino]amidino)urea

1-(4-[3-methylquinolino]amidino)urea

1-(1-isoquinolinoamidino)urea

                  TABLE 1-a                                                       ______________________________________                                         ##STR9##                                                                     R.sub.a           R.sub.5  R.sub.6                                            ______________________________________                                         ##STR10##        H        CH.sub.3                                            ##STR11##        H        C.sub.2 H.sub.5                                     ##STR12##        H        CH.sub.3                                            ##STR13##        H        C.sub.2 H.sub.5                                     ##STR14##        H        CH.sub.3                                            ##STR15##        H        C.sub.2 H.sub.5                                     ##STR16##        H        CH.sub.3                                            ##STR17##        H        CH.sub.3                                            ##STR18##        H        H                                                   ##STR19##        H        CH.sub.3                                            ##STR20##        H        C.sub.2 H.sub.5                                     ##STR21##        H        CH.sub.3                                            ##STR22##        CH.sub.3 CH.sub.3                                            ##STR23##        H        CH.sub.3                                            ##STR24##        H        C.sub.2 H.sub.5                                     ##STR25##        H        CH.sub.3                                            ##STR26##        CH.sub.3 CH.sub.3                                            ##STR27##        H        C.sub.2 H.sub.5                                     ##STR28##        H        H                                                   ##STR29##        H        CH.sub.3                                            ##STR30##        H        H                                                   ##STR31##        H        CH.sub.3                                            ##STR32##        H        C.sub.2 H.sub.5                                     ##STR33##        H        H                                                   ##STR34##        H        CH.sub.3                                            ##STR35##        H        H                                                   ##STR36##        H        CH.sub.3                                            ##STR37##        H        C.sub.2 H.sub.5                                     ##STR38##        H        OCH.sub.3                                           ##STR39##        CH.sub.3 CH.sub.3                                            ##STR40##        CH.sub.3 C.sub.2 H.sub.5                                     ##STR41##        H        H                                                   ##STR42##        H        CH.sub.3                                            ##STR43##        H        C.sub.2 H.sub.5                                     ##STR44##        H        H                                                   ##STR45##        H        CH.sub.3                                            ##STR46##        H        C.sub.2 H.sub.5                                     ##STR47##        H        OCH.sub.3                                           ##STR48##        CH.sub.3 CH.sub.3                                            ##STR49##        CH.sub.3 C.sub.2 H.sub.5                                     ##STR50##        H        H                                                   ##STR51##        H        CH.sub.3                                            ##STR52##        H        C.sub.2 H.sub.5                                     ##STR53##        H        CH.sub.3                                            ##STR54##        H        H                                                   ##STR55##        H        CH.sub.3                                            ##STR56##        H        C.sub.2 H.sub.5                                     ##STR57##        H        CH.sub.3                                            ##STR58##        CH.sub.3 CH.sub.3                                            ##STR59##        H        CH.sub.3                                            ##STR60##        H        C.sub.2 H.sub.5                                     ##STR61##        H        CH.sub.3                                            ##STR62##        H        H                                                   ##STR63##        H        CH.sub.3                                            ##STR64##        CH.sub.3 CH.sub.3                                            ##STR65##        H        CH.sub.3                                            ##STR66##        H        C.sub.2 H.sub.5                                     ##STR67##        CH.sub.3 CH.sub.3                                            ##STR68##        H        H                                                   ##STR69##        H        CH.sub.3                                            ##STR70##        CH.sub.3 CH.sub.3                                            ##STR71##        H        C.sub.2 H.sub.5                                     ##STR72##        H        H                                                   ##STR73##        H        CH.sub.3                                            ##STR74##        H        H                                                   ##STR75##        H        CH.sub.3                                            ##STR76##        H        C.sub.2 H.sub.5                                     ##STR77##        H        H                                                   ##STR78##        H        CH.sub.3                                            ##STR79##        H        H                                                   ##STR80##        H        CH.sub.3                                            ##STR81##        H        C.sub.2 H.sub.5                                     ##STR82##        H        OCH.sub.3                                           ##STR83##        CH.sub.3 CH.sub.3                                            ##STR84##        CH.sub.3 C.sub.2 H.sub.5                                     ##STR85##        H        H                                                   ##STR86##        H        CH.sub.3                                            ##STR87##        H        C.sub.2 H.sub.5                                     ##STR88##        H        H                                                   ##STR89##        H        CH.sub.3                                            ##STR90##        H        C.sub.2 H.sub.5                                     ##STR91##        CH.sub.3 CH.sub.3                                            ##STR92##        H        OCH.sub.3                                           ##STR93##        H        CH.sub.3                                            ##STR94##        CH.sub.3 CH.sub.3                                            ##STR95##        C.sub.2 H.sub.5                                                                        C.sub.2 H.sub.5                                     ##STR96##        CH.sub.3 CH.sub.3                                            ##STR97##        H        C.sub.2 H.sub.5                                     ##STR98##        H        H                                                   ##STR99##        H        CH.sub.3                                            ##STR100##       H        H                                                   ##STR101##       H        CH.sub.3                                            ##STR102##       H        C.sub.2 H.sub.5                                     ##STR103##       H        H                                                   ##STR104##       H        CH.sub.3                                            ##STR105##       H        H                                                   ##STR106##       H        CH.sub.3                                            ##STR107##       CH.sub.3 CH.sub.3                                            ##STR108##       H        CH.sub.3                                            ##STR109##       H        C.sub.2 H.sub.5                                     ##STR110##       CH.sub.3 CH.sub.3                                            ##STR111##       H        H                                                   ##STR112##       H        CH.sub.3                                            ##STR113##       H        CH.sub. 3                                           ##STR114##       H        H                                                   ##STR115##       H        CH.sub.3                                            ##STR116##       H        C.sub.2 H.sub.5                                     ##STR117##       H        CH.sub.3                                            ##STR118##       CH.sub.3 CH.sub.3                                            ##STR119##       H        CH.sub.3                                            ##STR120##       H        C.sub.2 H.sub.5                                     ##STR121##       H        CH.sub.3                                            ##STR122##       H        H                                                   ##STR123##       H        CH.sub.3                                            ##STR124##       CH.sub.3 CH.sub.3                                            ##STR125##       H        CH.sub.3                                            ##STR126##       H        C.sub.2 H.sub.5                                     ##STR127##       CH.sub.3 CH.sub.3                                            ##STR128##       H        H                                                   ##STR129##       H        CH.sub.3                                            ##STR130##       H        C.sub.2 H.sub.5                                     ##STR131##       H        H                                                   ##STR132##       H        CH.sub.3                                            ##STR133##       H        C.sub.2 H.sub.5                                     ##STR134##       CH.sub.3 CH.sub.3                                            ##STR135##       H        OCH.sub.3                                           ##STR136##       H        CH.sub.3                                            ##STR137##       CH.sub.3 CH.sub.3                                            ##STR138##       C.sub.2 H.sub.5                                                                        C.sub.2 H.sub.5                                     ##STR139##       H        CH.sub.3                                            ##STR140##       H        H                                                   ##STR141##       H        CH.sub.3                                            ##STR142##       H        C.sub.2 H.sub.5                                     ##STR143##       CH.sub.3 CH.sub.3                                            ##STR144##       H        OCH.sub.3                                           ##STR145##       H        CH.sub.3                                            ##STR146##       CH.sub.3 CH.sub.3                                            ##STR147##       C.sub.2 H.sub.5                                                                        C.sub.2 H.sub.5                                     ##STR148##       H        C.sub.2 H.sub.5                                     ##STR149##       H        CH.sub.3                                            ##STR150##       H        C.sub.2 H.sub.5                                     ##STR151##       H        CH.sub.3                                            ##STR152##       H        C.sub.2 H.sub.5                                     ##STR153##       H        CH.sub.3                                            ##STR154##       H        C.sub.2 H.sub.5                                     ##STR155##       H        CH.sub.3                                            ##STR156##       H        C.sub.2 H.sub.5                                     ##STR157##       H        CH.sub.3                                            ##STR158##       H        C.sub.2 H.sub.5                                     ##STR159##       CH.sub.3 H                                                   ##STR160##       C.sub.2 H.sub.5                                                                        H                                                   ##STR161##       CH.sub.3 H                                                   ##STR162##       C.sub.2 H.sub.5                                                                        H                                                   ##STR163##       CH.sub.3 H                                                   ##STR164##       C.sub.2 H.sub.5                                                                        H                                                   ##STR165##       CH.sub.3 H                                                   ##STR166##       C.sub.2 H.sub.5                                                                        H                                                   ##STR167##       CH.sub.3 H                                                   ##STR168##       C.sub.2 H.sub.5                                                                        H                                                   ##STR169##       H                                                                                       ##STR170##                                         ##STR171##       H                                                                                       ##STR172##                                         ##STR173##       H                                                                                       ##STR174##                                         ##STR175##       H                                                                                       ##STR176##                                         ##STR177##       CH.sub.3                                                                                ##STR178##                                         ##STR179##       CH.sub.3                                                                                ##STR180##                                         ##STR181##       H                                                                                       ##STR182##                                         ##STR183##       H                                                                                       ##STR184##                                         ##STR185##       H                                                                                       ##STR186##                                         ##STR187##       CH.sub.3                                                                                ##STR188##                                         ##STR189##       H                                                                                       ##STR190##                                         ##STR191##       H                                                                                       ##STR192##                                         ##STR193##       H                                                                                       ##STR194##                                         ##STR195##       H                                                                                       ##STR196##                                         ##STR197##       H                                                                                       ##STR198##                                         ##STR199##       H                                                                                       ##STR200##                                         ##STR201##       H                                                                                       ##STR202##                                         ##STR203##       H                                                                                       ##STR204##                                         ##STR205##       H                                                                                       ##STR206##                                         ##STR207##       H                                                                                       ##STR208##                                         ##STR209##       H                                                                                       ##STR210##                                         ##STR211##       H                                                                                       ##STR212##                                         ##STR213##       H                                                                                       ##STR214##                                         ##STR215##       CH.sub.3                                                                                ##STR216##                                         ##STR217##       H                                                                                       ##STR218##                                         ##STR219##       H                                                                                       ##STR220##                                         ##STR221##       H                                                                                       ##STR222##                                         ##STR223##       H                                                                                       ##STR224##                                         ##STR225##       H                                                                                       ##STR226##                                         ##STR227##       H                                                                                       ##STR228##                                         ##STR229##       H                                                                                       ##STR230##                                         ##STR231##       CH.sub.3                                                                                ##STR232##                                         ##STR233##       CH.sub.3                                                                                ##STR234##                                         ##STR235##       H                                                                                       ##STR236##                                         ##STR237##       H                                                                                       ##STR238##                                         ##STR239##       H                                                                                       ##STR240##                                        ______________________________________                                    

The compounds of this invention may be prepared by the following generalsynthesis:

Condensation of cyanamide and a heterocyclic amine results in thecorresponding heterocyclic substituted guanidine.

The reaction is preferably carried out on the amino heterocyclic salteither in a polar medium or neat and using increased temperatures. Thesalt used may be any acid addition amine salt but preferably the salt ofa mineral acid. The polar medium may be aqueous, partially aqueous or anon-aqueous solution. It is convenient to choose a solvent that willreflux at the desired reaction temperature. The more preferred solventsare water or alcohol but other solvents may be used such as DMSO,diethyleneglycol, ethyleneglycol, tetrahydrofuran, dimethylformamide,etc. The most preferred solvent is a mildly acidic solvent which isnon-nucleophilic such as phenol, cresol, xylenol, etc. The reactionshould also be carried out at a temperature which is high enough so thatcondensation takes place readily, but not sufficient to decompose theguanidine formed. The reaction temperature can vary from roomtemperature to about 250° C. although it is preferable to run thereaction at temperatures from about 50° C. to 150° C. The guanidine saltwhich is formed can be converted to the free base with a metal hydroxideor alkoxide solution. The isolation of the desired guanidine can becarried out by any method known in the art.

When the heterocyclic guanidine is reacted with a substituted isocyanateof the formula R'NCO, then the product formed is a 1-substitutedheterocyclic amidino-3-R'-urea. This reaction is preferably carried outin a non-protic medium using solvents such as benzene, toluene, xylene,THF, etc. The reaction may be conducted at room temperature or as aboveat raised temperatures.

The following reaction equations illustrate this synthesis using2-pyridyl as an exemplary heterocycle: ##STR241## where: HX' is amineral acid and R₅ is other than hydrogen.

When R substitution is desired in the R₂ -position, it is convenient tocarry out the condensation using the appropriately N-substitutedheterocycle. Thus, for example, 2-pyridyl-N-methylamine would result inthe 1-(2-pyridyl)-1-methyl-quanidine. This is then reacted as above withthe isocyanate to form the amidinourea. ##STR242##

It is convenient to use t-butylisocyanate in the above reaction wheresubstitution is not desired in the R₃ -position. This may then beselectively hydrolyzed off.

When substitution is desired in the R₃ or R₄ -position, it is convenientto carry out the condensation using the appropriately substitutedcyanamide of the formula NCNHR₃. Thus, for example, methylcyanamidecondensed with 2-pyridylamine would result in the corresponding1-(2-pyridyl)-3-methylguanidine. This is then reacted as above with theisocyanate to form the amidinoureas. ##STR243##

Condensation of a heterocyclic amine with benzoylthiourea results in the1-heterocycle-3-benzoylthiourea. This may then be hydrolyzed to the1-heterocycle thiourea and treated with iodomethane to obtain the1-heterocyclic-2-methyl-pseudothiouronium iodide. When the latter istreated with an amine of the formula NH₂ R₃, the resulting product is a1-heterocyclic-3-R-guanidine which may then be reacted as above to formthe amidinourea. ##STR244##

These compounds may also be prepared by condensing the desired aminoheterocycle with a substituted isothiourea. The resulting guanidinecompounds are reacted with an isocyanate as above to obtain theamidinourea. ##STR245##

The heterocyclic amine may also be condensed with a thiocyanate of theformula SCNR. The reaction product is a thiourea which is then treatedwith iodomethane and reacted with an amine of the formula NH₂ R toobtain the desired guanidine. ##STR246##

When substitution is desired in the R₄ -position, the heterocyclic amineis condensed with t-butyl thiocyanate (SCN-t-butyl) to form thethiourea. The t-butyl group is then hydrolyzed off with conc. HCl. Theproduct is reacted with an isocyanate to obtain the carbamylthiourea,which is treated with iodomethane and reacted with an amine of theformula NHR₄ to obtain the desired amidinourea. ##STR247##

When R₅ and R₆ substitution is desired the appropriate guanidine isreacted with an acid chloride of the amine of the formula ##STR248## Thelatter is made by the reaction of the amine of the formula ##STR249##with phosgene in an inert solvent. The reaction of the acid chloride andguanidine is carried out in a polar medium and inert conditions atmoderate temperatures. ##STR250##

When substitution in the R₅ and R₆ positions is not desired, the desiredheterocyclic amidinourea may be prepared by the acid hydrolysis of the1-(heterocyclic)-3-cyano guanidine. ##STR251##

The cyano guanidine may be prepared by the reaction of the aminoheterocycle with an N-cyano-O-R_(L) -psuedourea. ##STR252## R_(L)represents a suitable leaving group, such as a substituted phenyl group.

Appropriately desired end products having various R₂, R₃, R₄, R₅ and R₆substituents may be prepared at various steps of synthesis usingsuitable reactions in order to convert one group to another.

The starting heterocyclic primary amines are either known, or may beprepared by known techniques. Thus, chlorination or bromination of aprimary or secondary heterocyclic substituted amine may be carried outin acetic acid, or in the presence of a small amount of iodine dissolvedin an inert solvent such as carbon tetrachloride. A solution of chlorineor bromine is then added while the temperature is held near 0° C.Iodination may also be carried out by known methods using iodinemonochloride (ClI).

Alkylation may be carried out on an amine using an alkyl halide andaluminum chloride under Friedel-Crafts conditions to obtain desiredalkyl substitution.

Nitration may be carried out using fuming nitric acid at about 0° C.

A nitro compound may be hydrogenated to the corresponding amine whichmay then be diazotized and heated in an alcohol medium to form thealkoxy compound.

An amino compound may also be diazotized to the diazonium fluoroboratewhich is then thermally decomposed to the fluoro compound. Diazotizationfollowed by a Sandmeyer type reaction may yield the bromo, chloro oriodo compound.

A chloro, bromo or iodo compound may also be reacted withtrifluoromethyliodide and copper powder at about 150° C. indimethylformamide to obtain a trifluoromethyl compound [TetrahedronLetters: 47, 4095 (1959)].

A halo compound may also be reacted with cuprous methanesulfinate inquinoline at about 150° C. to obtain a methylsulfonyl compound.

When it is desired that the final product contain a hydroxy substitutedheterocyclic group, it is preferred that the starting heterocyclic aminecontain the corresponding acyloxy or aralkyloxy groups. These may beprepared in the usual fashion by acylating the starting hydroxyheterocyclic compoound with acyl halide or anhydride in the presence ofa tertiary amine or aralkylating with an aralkyl halide or sulfate. Ofcourse the amine function would be protected in the customary manner.Hydrogenolysis of the aralkyl group to the desired hydroxy compound maythen take place after the formation of the amidinourea. This may beaccomplished with a metal catalyst (Pd/C, Pt etc.) in a polar medium(ethanol, THF, etc.) for example, sodium in liquid ammonia. Thus, forexample, the 4-hydroxy-2-pyridyl amidinourea compound may be preparedfrom the corresponding 4-benzyloxy-2-pyridyl compound. The hydroxycompounds may also be prepared by hydrolysis of the acyl or aralykoxycompounds with acid.

When it is desired that the final product contain an N- or S-oxide ofthe group R₁, starting materials containing this function may be used orthe final products may be oxidized using a peroxide, for example, anorganic peracid, such as, m-chlorobenzoic acid.

Reactions may also be carried out at other stages of synthesis dependingon the substituents present and the substituents desired and variouscombinations of the foregoing reactions will be determined by oneskilled in the art in order that the desired product results. Thus, aphenylguanidine or amidinourea may be halogenated or nitrated as above,etc.

The following examples illustrate the preparation of the heterocyclicamidino substituted ureas of this invention and are not to be construedas a limitation thereof.

EXAMPLE I The Preparation of1-Propylcarbamoyl-3-(2-pyridylmethyl)guanidine dihydrochloride

1-(2-Pyridylmethyl)guanidine sulfate

2-Aminomethylpyridine (54.07 g) is added to a vigorously stirredsolution of 2-methyl-2-thiopseudouronium sulfate (69.60 g) in 200 ml ofH₂ O. The stirred mixture is carefully warmed while being flushed with acontinuous stream of N₂. Alkaline KMnO₄ is used to scavenge for evolvedmethyl mercaptan. The mixture is stirred at 65° C. over the weekendresulting in a bright yellow solution which is heated to boiling. Afterrefluxing for 30 minutes the solution is filtered while hot andevaporated to dryness under reduced pressure. The residue is a brilliantgreen crystalline solid which is taken up in hot aqueous methanol. Uponcooling, crystals separate and the solid is collected and dried in vacuoyielding 65.6 g of crystals, MP 206°-207° C. The crystalline solid istaken up in boiling water; a portion of Darco G-60 is added and themixture filtered. The filtrate is concentrated and cooled. Thecrystalline precipitate is collected, washed with methanol and dried,yielding 8.6 g of a white crystalline product, MP 208°-209° C. which isdetermined to be the desired 1-(2-pyridylmethyl)guanidine sulfate.

1-(Propylcarbamoyl)-3-(2-pyridylmethyl)guanidine dihydrochloride

1-(2-Pyridylmethyl)guanidine sulfate (13.15 g) and 10 ml of CHCl₃ areadded to a vigorously stirred solution of 50% aqueous NaOH (5.2 g) andTHF (15 ml). The mixture is stirred at RT for 2 hours. A 5 gram portionof solid anhydrous Na₂ SO₄ is added and the mixture is stirred at roomtemperature for an additional hour. 100 ml of CHCl₃ and 50 ml of CH₃ CNare added to the vigorously stirred mixture followed by an additional 5g portion of Na₂ SO₄. A solution of N-propyl isocyanate (5.11 g) and 75ml of THF is added dropwise to the mixture and stirred at RT overnight.The solvent is evaporated in vacuo and the dark residue is mixed with200 ml of CHCl₃, 100 ml of saturated aqueous sodium chloride and 50 mlof water. The organic layer is separated and the aqueous layer is washedwith an additional 200 ml portion of CHCl₃. The organic phases arecombined, washed with 70 ml of aqueous sodium chloride containing 5 mlof 50% aqueous NaOH, dried, filtered and concentrated in vacuo. Theconcentrate is acidified with ethereal HCl and evaporated to drynessunder reduced pressure. The residue is taken up in boiling methanol,treated with Darco G-60 and filtered. The filtrate is concentrated toapproximately 200 ml on a hotplate and diluted with approximately 200 mlof acetonitrile with continued heating. The hot solution is allowed tocool and the resultant precipitate collected, washed with acetonitrileand absolute ethanol. The solid is suspended in 200 ml of warm absoluteethanol, filtered while hot and dried in vacuo at 55° C. overnight togive 6.90 g of a blue white solid, MP 216°-218° w/dec.

EXAMPLE II The Preparation of 1-Carbamoyl-3-(4-pyridylmethyl)guanidinedihydrochloride

1-Cyano-3-(4-pyridylmethyl)-guanidine

4-Amino methyl pyridine (16.22 g) is added to a stirred suspension ofN-cyano-O-(m-cresyl)pseudourea (27.51 g) in 200 ml of isopropanol. Themixture is heated to boiling and refluxed for five hours. The reactionmixture is filtered and the filtrate evaporated under reduced pressure.The residue is stirred in 250 ml of chloroform overnight, the solventremoved under reduced pressure, treated with 250 ml of diethyl ether,the ether decanted and the residual gum treated with 200 ml of 5% HCland stirred at room temperature for one hour. The mixture is filtered,extracted twice with 200 ml portions of diethyl ether and cooled toabout 5° C. The solution is treated carefully with a 50% aqueous sodiumhydroxide solution to a pH of 9 and extracted twice with 250 ml portionsof methylene chloride. The organic extracts are combined, dried,filtered and evaporated to dryness under reduced pressure leaving asmall amount of colored liquid. The aqueous layer is saturated withsodium chloride and re-extracted. After drying, the extracts areevaporated under reduced pressure. The aqueous phase is concentratedunder reduced pressure and diluted with ethanol. The precipitated saltsare removed by filtration and the filtrate concentrated under reducedpressure. The residue is azeotroped with 150 ml of toluene. The residueis stirred with 250 ml of isopropanol, filtered and evaporated underreduced pressure. The residue is triturated with 250 ml of isopropanoland filtered. The filtrate is dried, filtered, and evaporated underreduced pressure. The residue is taken up in a methanol/ethyl acetatemixture and allowed to stand. After trituration, the mixture is stirredin water overnight, the precipitate then collected and dried in air. Theoff-white solid is recrystallized from water yielding 12.10 g of paleyellow crystals which are dried in vacuo (55° C.), MP 92°- 93° C. IR andelemental analysis indicate the desired guanidine.

1-Carbamoyl-3-(4-pyridylmethyl)guanidine dihydrochloride

Concentrated HCl (21 ml) is added to a mixture of1-cyano-3-(4-pyridylmethyl)guanidine (10.0 g) in 500 ml of isopropanol.A pale yellow precipitate forms. The stirred suspension is heated on asteam bath and boiled for ten minutes. The solvent is evaporated underreduced pressure and the residual solid treated with 25 ml ofconcentrated HCl. The solution is heated on a steam bath for severalminutes and diluted with isopropanol (50 ml) and allowed to cool. Theresulting solid is collected and dred in air, extracted into 900 ml ofmethanol, which is filtered, and concentrated on a not plate. The hotsolution is diluted with ethyl acetate and concentrated further. A whiteprecipitate forms on cooling which is collected and dried in air givingthe desired amidinourea dihydrochloride, MP 208°-209.5° C. w/dec.

EXAMPLE III The Preparation of1-Propylcarbamoyl-3-(2-[2-pyridyl]ethyl)guanidine

2-(2-Guanidino ethyl)pyridine

2-(2-Aminoethyl)pyridine (50.0 g) is added to a vigorously stirredsolution of 2-methyl-2-thiopseudouronium sulfate (57.07 g) in 165 ml ofH₂ O. The mixture is warmed slowly to boiling with a continuous flow ofN₂ passed through the mixture. The evolved methyl sulfide is scavengedusing alkaline potassium permanganate solution (25 g KMnO₄ in 250 ml of10% aqueous sodium hydroxide). The solution is refluxed for one hour andthen allowed to cool. The solid is stripped off under reduced pressureand the residue crystallizes on standing. The crystalline product istaken up in boiling 95% ethanol and filtered while hot. The hot solutionis diluted with 100 ml of acetonitrile and filtered hot. The filtrate isboiled down and diluted with acetonitrile. After cooling, the whitecrystalline product is collected, washed with ethanol and acetonitrileand dried to yield 64.35 g of the desired guanidine sulfate, MP111°-112° C. The crystalline solid is extracted with boiling absoluteethanol and the hot extract filtered through a Celite mat andconcentrated. The white solid is collected and dried in vacuo, MP152°-153° C.

1-Propylcarbamoyl-3-(2-[2-pyridyl]ethyl)guanidine

Anhydrous Na₂ SO₄ (20 g) is added to a stirred mixture of2-(2-guanidinoethyl)pyridine sulfate, and 50% aqueous NaOH (12.0 g) in250 ml of THF and stirred at room temperature for four and one halfhours. A solution of propyl isocyanate (12.77 g) and 250 ml of THF isadded dropwise to the reaction mixture and stirred at room temperature.The solvent is evaporated under reduced pressure and the residue takenup in a mixture of H₂ O (250 ml) and methylene chloride (400 ml). Afterstirring at RT for 30 minutes, the organic phase is separated, and theaqueous layer extracted with methylene chloride (250 ml). The organiclayers are combined, dried, filtered, and evaporated to near drynessunder reduced pressure. Prior to evaporation the solution is filtered toremove small amounts of particulate material and then evaporated todryness under reduced pressure. The residue is treated with methanolichydrogen bromide and the solution evaporated to dryness under reducedpressure. The residual solid is crystallized from acetonitrile,collected, washed with acetonitrile and dried in air to yield 40.6 g ofthe dihydrobromide salt of the desired guanidine, M.P. 144°-145° C.w/dec.

EXAMPLE IV The Preparation of1-(Propylcarbamoyl)-3-(4-pyridylmethyl)guanidine succinate

Anhydrous Na₂ SO₄ is added to a stirred mixture of1-(4-pyridylmethyl)guanidine carbonate monohydrate (12.0 g) and 50%aqueous NaOH (5.12 g) in 75 ml of DMSO which has been stirred at RT forfive hours. The mixture is stirred at room temperature for an additionalhour and then a solution of propyl isocyanate (5.11 g) in 25 ml of THFis added dropwise. The mixture is stirred at RT over the weekend, afterwhich the THF is removed under reduced pressure. The residue is pouredinto 500 ml of H₂ O and the solution extracted twice with 300 mlportions of chloroform. The extracts are combined and dried, washed with150 ml of saturated aqueous sodium chloride diluted with 100 ml of H₂ O.The organic phase is separated, dried, filtered and evaporated in vacuoto yield a yellow liquid which is taken up in ethyl acetate and treatedwith ethereal HCl. The solvent is stripped off under reduced pressureand the residue is taken up in hot ethyl acetate containing a smallamount of methanol. The solution is diluted with ethyl acetate,concentrated on a steam bath and cooled. A precipitate is collected anddried in vacuo to yield 4.35 g of a yellow solid which is crystallizedfrom methanol/acetonitrile and dried to give a pale yellow powder, MP174°-176° C., which is confirmed to be the desired 4-pyridyl guanidinedihydrochloride salt.

The dihydrochloride salt is dissolved in saturated aqueous sodiumchloride, the pH adjusted to 10 with 50% aqueous sodium hydroxidesolution and the resulting suspension extracted three times withchloroform. The extracts are combined, dried, filtered and evaporated todryness under reduced pressure. The residual yellow oil is combined withsuccinic acid and the mixture dissolved in a minimum volume of boilingisopropanol and allowed to stand in the cold. A white crystalline solidis collected, washed with isopropanol and dried in vacuo overnight. Thematerial is recrystallized from acetonitrile/methanol and dried in vacuoto give 74% of the succinate salt as a white solid, MP 159°-160° C.

EXAMPLE V The Preparation of1-[3-(2-Pyridyl)propyl]-3-(propylcarbamoyl)guanidine dihydrochloride

3-(2-Pyridyl)propyl guanidine

A mixture of 3-(2-pyridyl)propylamine (13.55 g) and2-methyl-2-thiopseudourea sulfate (13.85 g) in 40 ml of H₂ O is stirredunder reflux for one hour and then at RT for three days. Aqueous sodiumhypochlorite solution is used to scavenge for evolved methyl mercaptan.The solution is filtered, diluted with a small volume of ethanol andconcentrated under reduced pressure. The white solid residue isextracted into boiling aqueous ethanol, the solution is filtered whilehot and allowed to cool. The white solid is collected, washed withethanol and dried in air. The white solid is extracted with one liter ofboiling 95% ethanol. The filtrate from the isolation of the solid isstripped to dryness under reduced pressure and the resulting residue istaken up in 95% ethanol and added to the above extract. The mixture isfiltered to yield a white solid, MP 225°-227° w/dec. The filtrate isconcentrated under reduced pressure and the resulting residue taken upwith 95% ethanol containing acetonitrile. The solvent is evaporated invacuo and the residue is taken up in boiling methanol, diluted withacetonitrile and allowed to stand at room temperature. The resultingsolid is collected, washed with acetonitrile and ethanol and dried inair. This material contains unreacted starting material. This solid istreated with 20% nitric acid, diluted with ethanol, and concentrated invacuo. The concentrate is diluted with 125 ml of absolute ethanol andcooled. The white precipitate is collected, washed thoroughly withabsolute ethanol and dried in air to yield 4.4 g of the desired3-(2-pyridyl)propyl guanidine dinitrate MP 172°-174° C.

The filtrate from above is evaporated and the residue treated with 20%aqueous nitric acid, diluted with approximately 10 volumes of ethanoland stirred at room temperature for 30 minutes. The solvent is removedin vacuo and the residue triturated in boiling absolute ethanol. Theslurry is cooled and the solid collected, washed with absolute ethanoland dried in vacuo yielding 13.96 g of an off-white powder confirmed asthe guanidine dinitrate MP 174°-178° C.

1-[3-(2-Pyridyl)propyl]-b 3-(propylcarbamoyl)guanidine dihydrochloridehydrate

A 50% aqueous sodium hydroxide solution (6.40 g) is added slowly to asuspension of 3-(2-pyridyl)propyl guanidine dinitrate (12.17 g) in 200ml of THF followed by the addition of 200 ml of THF. The suspension isstirred vigorously at RT for 20 hours after which anhydrous Na₂ SO₄ (25g) is added to the mixture. Stirring is continued for one half hourafter which a solution of propyl isocyanate (3.40 g) in 100 ml of THF isadded dropwise to the mixture. The mixture is stirred at RT overnight.The solvent is stripped off under reduced pressure and the residue takenup in a mixture of methylene chloride (250 ml), H₂ O (150 ml) andsaturated sodium chloride solution (150 ml). The organic phase isseparated and the aqueous layer extracted with methylene chloride. Theorganic layers are combined, dried, filtered, and treated withmethanolic HCl, and stripped to dryness under reduced pressure. Thepartially crystalline residue is stirred at room temperature for tenminutes in a mixture of H₂ O (150 ml), 10% HCl (50 ml), and methylenechloride (100 ml). The organic layer is separated and discarded. Theaqueous phase is adjusted to a pH of 7 with solid NaHCO₃ and extractedtwice with methylene chloride. Extracts are combined, dried, filteredand concentrated under reduced pressure. The concentrate is acidifiedwith etherial HCl after dilution with acetonitrile (100 ml) and thenstripped dry under reduced pressure. The residue is taken up in boilingabsolute ethanol, filtered hot through Celite, concentrated and dilutedwith a small volume of ethyl acetate and concentrated to a syrup.Trituration initiated crystallization of the syrup which is then dilutedwith about 1 volume of acetonitrile and then allowed to stand. Thecrystalline mass is broken up and collected, washed with coldacetonitrile, ethyl acetate solution (1:1) and dried in vacuo to yield6.88 g of crystals MP 96°-98° C. of the dihydrochloride hydrate salt.

EXAMPLE VI Preparation of1-Methyl-3-(propylcarbamoyl)-1-(2-[2-pyridyl]ethyl)guanidinedihydrochloride

A mixture of 1-methyl-1-(2-[2-pyridyl]ethyl)guanidine sulfatehemi-hydrate (16.23 g) and 50% aqueous sodium hydroxide (5.60 g) in 300ml of THF is stirred at room temperature for one and one half hoursafter which anhydrous Na₂ SO₄ (25 g) is added to the mixture. Themixture is stirred at RT for one hour after which a solution of propylisocyanate (5.96 g) in 100 ml of methylene chloride is added dropwise.The mixture is stirred at RT overnight. The solvent is removed underreduced pressure and the residue taken up in a mixture of H₂ O (100 ml)and methylene chloride (500 ml). The mixture is shaken several minutesafter which the organic layer is separated. The aqueous layer is washedwith methylene chloride (250 ml) and the organic layers are combined,dried, filtered and concentrated under reduced pressure. The concentrateis treated with etheral HCl and stripped to dryness. The residue iscrystallized from acetonitrile/methanol and the product collected,washed with acetonitrile, and dried in vacuo to yield 10.21 g of a whitesolid confirmed to be the 1-methyl-3-propyl carbamoyl guanidinedihydrochloride. MP 200°-201° C. The concentration of the filtrateafforded 8.30 g of a second crop of white crystals, MP 194°-196° C.

EXAMPLE VII The Preparation 1-Carbamoyl-3-(2-pyridylmethyl)guanidinedihydrochloride

1-Cyano-3-(2-pyridylmethyl)guanidine

A mixture of 2-amino methyl pyridine (10.91 g) and1-cyano-2-(3-tolyl)pseudourea (17.52 g) in 250 ml of isopropanol isstirred at reflux under a nitrogen atmosphere for 5 hours. The reactionmixture is allowed to cool to room temperature and the solvent isremoved in vacuo. The dark green residual oil is stirred in 250 ml ofdiethyl ether. The resultant solid is collected and washed with ether,and ground to a paste in 100 ml of diethyl ether. The solid is filtered,washed with ether and dried in air. The solid is taken up in boilingacetone and filtered hot, concentrated in a hot plate and cooled. Theprecipitate is collected and recrystallized from acetone to yield 7.08 gof the cyano guanidine, MP 144° C.

1-Carbamoyl-3-(2-pyridylmethyl)guanidine dihydrochloride

Concentrated HCl (15.4 ml) is added to a stirred solution of1-cyano-3-(2-pyridylmethyl)guanidine (4.50 g) in 310 ml of isopropanol.The reaction mixture is stirred at room temperature overnight. Thesolvent is concentrated in vacuo and the residue treated with 1.8 litersof boiling ethanol. The resulting suspension is stirred and heated whileadding small portions of water until most of the solid has dissolved.The solution is filtered through Celite, diluted to 2 liters withabsolute ethanol and concentrated on a hot plate and cooled. The firstcrop of crystals, MP 214°-215° C. w/dec, and the second crop ofcrystals, MP 215°-216° C. w/dec, obtained by concentration of thefiltrate, were combined to give 2.60 g of the carbamoyl guanidine as agrey-green solid. The grey-green solid is dissolved in boiling ethanol,treated with Darco G-60 and filtered. The filtrate is boiled down on ahotplate and the white crystalline precipitate is collected, washed withabsolute ethanol and dried in air yielding 1.77 g of the desired productMP 214°-216° C. w/dec.

This invention further encompasses a novel method for the treatment ofhuman and veterinary spasmolytic disorders, arrhythmic conditions,hypertensive conditions, gastrointestinal disorders and protozoalinfestations by the administration of a compound of the Formulae I-VII.

The compounds of this invention have a useful degree of gastricantisecretory activity and are effective in reducing the volume and theacidity of the gastric fluid in humans and mammals. Further, thesecompounds produce a considerable spasmolytic action on thegastrointestinal musculature, i.e., they reduce the peristaltic actionof the gastrointestinal musculature which is manifested by a delay ingastric emptying time. It should further be noted that these compoundsare also characterized by their low acute oral toxicity.

In particular, the heterocyclic amidino substituted ureas as hereindescribed are useful in the treatment of such gastrointestinal disordersand diseases as duodenal ulcer and peptic ulcer. The compounds of thisinvention are also useful as antidiarrheal agents.

The instant compounds may be used alone or in combination with otherknown antacids such aluminum hydroxide, magnesium hydroxide, magnesiumtrisilicate, aluminum glycinate, calcium carbonate and the like.

The compounds of this invention possess blood-pressure-loweringactivities and are also useful as anti-hypertensive agents.

The compounds described herein also possess useful anti-arrhythmicproperties as well as useful local anesthetic properties.

Various tests in animals have been carried out to show the ability ofthe compounds of this invention to exhibit reactions that can becorrelated with activity in humans. These tests involve such factors asthe effect of the heterocyclic amidino substituted ureas on gastricsecretion, their spasmolytic effect, their blood-pressure-loweringeffect, and determination of their toxicity. It has been found that thecompounds of this invention, when tested in the above variety ofsituations, show a marked activity.

One such test is the gastric secretion test. This test is carried out asfollows: Shay rats are fasted for 4-8 hours and water is given ad lib.The rats are selected at random and separated into groups of ten. Theanimals are treated intraduodenally (I.D.) with the test compound or thevehicle immediately subsequent to the ligation of the stomach at thepyloric sphincter. The animals are sacrificed with chloroform at fourhours post-drug-administration, the stomach removed and its contentsassayed for volume, pH and total acids.

A second gastric secretion test is carried out on the dog. This isoutlined in the Handbook of Physiology, Section 6: Alimentary Canal,Volume II: Secretion; American Physiology Society, Washington, D.C.,1967.

It has been found that the compounds of this invention, when subjectedto the above gastric secretion tests, display marked ability to decreasegastric volume and gastric acidity. These tests are known to correlatewell with gastric activity in humans and are standard tests used todetermine antisecretory properties.

To determine the anti-ulcer effectiveness, the following test isemployed: Male Wistar rats (130-150 grams) are fasted for 24 hours, thengiven reserpine at 5 mg/kg i.p. Twenty-four hours later, the stomachsare removed and examined for ulceration. Ulcers are graded on a 0-4scale and the number of ulcers are recorded.

Determination of antispasmolytic properties can be carried out by theprocedure outlined by D. A. Brodie and S. K. Kundrats in their articleentitled "Effect of Drugs on Gastric Emptying in Rats," Fed. Proc.24:714 (1965). Acute toxicity is calculated according to the standardLicthfield-Wilcoxon procedure.

Various tests can be carried out in animal models to show the ability ofthe compounds of this invention to exhibit reactions that can becorrelated with antidiarrheal activity in humans. The following testsare considered to be standard tests used to determine antidiarrhealproperties. This correlation can be shown by the activities of compoundsknown to be clinically active.

1. Fecal output in rat: The oral ED₅₀ (that dose which would be expectedto reduce fecal output by 50%) is determined by a method described byBass et al., 1972. Briefly, the method involves dosing the rats andcollecting the fecal output over an 8-hour period (4 P.M.-midnight) withthe room darkened starting at 4:30 P.M.

Ref: Bass, P., Kennedy, J. A. and Willy, J. N.: Measurement of fecaloutput in rats. Am. J. Dig. Dis. 10:925-928, 1972.

2. Castor oil test in mice: Groups of mice are orally dosed with testcompound and a half hour later all mice are given 0.3 ml of castor oil.Three hours after castor oil administration, all mice are checked fordiarrhea and the dose of testing compound which protected 50% of themice from diarrhea is the ED₅₀ dose; 3. Castor oil test in rats: Thetest is conducted according to Niermegeers et al., 1972. The rat orallydosed with graded doses of test compound. One hour after dosing, eachanimal is challenged with 1 ml of castor oil orally. Fecal output isexamined 1, 2, 3, 4, 6 and 8 hours after castor oil. Absence of diarrheais the criterion of drug effectiveness.

Ref: Neimegeers, C. J. E., Lenaerts, F. M. and Janssen, P. A. J.Difenoxine, a potent, orally active and safe antidiarrheal agent inrats. Arzneim-Forschung (Drug Res.) 22, 516-518, 1972.

Tests in animals have also been carried out to show the ability ofcompounds of this invention to exhibit activity that can be correlatedwith antihypertensive action in humans. One such test is outlined byJacques de Champlain, Lawrence R. Krahoff and Julius Axelrod inCirculation Research XXIII:479 (1968). This testing method is known tocorrelate well with antihypertensive activity in humans and is astandard test used to determine antihypertensive properties. In view ofthe results of this test, the heterocyclic substituted amidino ureas ofthis invention can be considered to be active antihypertensive agents.

The heterocyclic substituted amidino ureas and thioureas of thisinvention are useful in the treatment of parasitic infestations of ahuman host, particularly parasitic protozoal infestations.

The heterocyclic substituted amidino ureas are also useful in theveterinary treatment of blood-residing parasitic diseases afflictingcattle, horses, sheep, pigs, dogs, chickens, turkeys and geese.

These compounds are useful in the treatment of veterinary diseasescaused by parasitic helminths, particularly Filaria, and by parasiticprotozoa, particularly Plasmodium and Babesia.

Microbiological tests can be carried out in model systems to show theability of the heterocyclic substituted amidino ureas of this inventionto exhibit activity that can be correlated with antiprotozoal activityin humans and animals. The following microbiological test can show theability of the compounds of this invention to inhibit parasiticprotozoal growth and reproduction.

ANTIMALARIAL BLOOD SMEAR TEST

Mice are injected intraperitoneally with 5,000,000 parasitized bloodcells from a donor. Groups of ten mice receive inoculations administeredsubcutaneously in doses ranging from 0.15 to 100 mg/kg, suspended in0.5% methecel solution (doses expressed as base). The compound ofinterest is repeatedly injected on the day of inoculation (Day 1), Day 2and Day 3. Blood smears are performed on Days 4, 5, 6 and 10 and thenumber of parasitic protozoa noted.

The compositions of the present invention can be prepared in formssuitable for administration by compounding an effective single doseamount of a compound of Formula I above, with known ingredientsgenerally employed in the preparation of therapeutic compositionsprovided as tablets, capsules, lozenges, pills, powders, granules,suspensions, oil and water, or water and oil emulsions of similar formswhich can be taken orally. The treatment of animals can be accomplishedby incorporating an effective amount of a compound of Formula I in theanimal diet with feed supplement or dissolved in the animal's fluidintake.

The compounds are readily absorbed into the blood stream from thestomach and intestines when taken orally. The preferred method oftreatment is, therefore, to give the drug orally which is also thesafest and most practical route of administration. Optional modes can beused where, for example, the human or animal is not eating or cannotswallow or has difficulty in swallowing, other methods of administrationwhich permit the drug to be absorbed in the gastrointestinal tract orwhich deliver a solution of the drug directly to the blood stream can beemployed.

The method of administration may also vary depending on the purpose ofadministration. For example, use as a prophylaxis or preventivetreatment, a pre-immunity suppressant or as treatment of infectedanimals can require different methods of treatment and dosage forms.

The dosage regimens in carrying out the methods of this invention arethose which insure maximum therapeutic response, bearing in mind, ofcourse, that in selecting the appropriate dosage in any specific case,consideration must be given to the patient's weight, general health,age, the severity of the disorder, and other factors which may influenceresponse to the drug. The average effective dose is between about 0.1 toabout 50 mg. per kg. of body weight with about 1.0 to about 10 mg/kgbeing preferred.

Further, the active heterocyclic amidino substituted urea may beadministered alone or in admixture with other agents having the same ordifferent pharmacological properties.

The following are detailed examples which show veterinary andpharmaceutical compositions containing the active compounds of Formula Iand serve to illustrate the preparation thereof:

EXAMPLE VIII

25 g of 1-[3-(2-Pyridyl)propyl]-3-(propylcarbamoyl)quanidinedihyrochloride 175 g of peanut oil are intimately mixed with each other.Portions of 200 mg. each of said mixture are filled into soft gelatincapsules thus containing 25 mg of the active compound. The capsules aresuitable for administration to humans and small animals for prophylacticor treatment of blood residing parasite diseases including malaria andheart worm.

EXAMPLE IX

Ten thousand tablets for oral use, each containing 50 mg are preparedfrom the following types and amounts of material:

    ______________________________________                                        Ingredients                 Grams                                             ______________________________________                                        1-Methyl-3-(propylcarbamoyl)-1-(2-[pyridyl]ethyl)                                                         500                                               guanidine dihydrochloride)                                                    Lactose U.S.P.              350                                               Potato Starch U.S.P.        346                                               ______________________________________                                    

The mixture is moistened with an alcoholic solution of 20 grams ofstearic acid and granulated through a sieve. The granulated material isadded to the following mixture.

    ______________________________________                                        Ingredient        Grams                                                       ______________________________________                                        Potato Starch U.S.P.                                                                            320                                                         Talcum            400                                                         Magnesium Stearate                                                                              500                                                         Lactose            64                                                         ______________________________________                                    

The mixture is thoroughly mixed and compressed into tablets. The tabletsare especially useful for human use.

EXAMPLE X

An elixir in which each 5 ml contains 50 mg of1-Carbamoyl-3-(2-pyridylmethyl)guanidine dihydrochloride is prepared bydiluting 750 ml of invert sugar with 100 ml of water and adding to this0.3 g of benzoic acid and 10 g of1-Propylcarbamoyl-3-(2-[2-pyridyl]ethyl)guanidine dihydrobromidehydrate. 100 ml of alcohol (U.S.P. containing 0.2 g of flavors) is addedand water is added to a total volume of 1 liter. The solution isthoroughly mixed, filtered and bottled. The preparation is useful foradministering to humans, small animals and avian species forprophylactic treatment in combatting helmenthic diseases.

EXAMPLE XI

Capsules are prepared as follows:

150 g of 1-(Propylcarbamoyl)-3-(4-pyridylmethyl)guanidine succinate

3 g magnesium stearate

2 g of finely divided silica sold under the trademark CAB-O-SIL byGodfrey L. Cabot, Inc., Boston, Mass., and

234 g of lactose.

The ingredients are thoroughly mixed with each other and the mixture isfilled in gelatin capsules. Each capsule contains 500 mg of thecomposition and thus 150 mg of the succinate salt. The capsules can beadministered to humans or small animals.

EXAMPLE XII

Tablets are prepared as follows:

100 g of 1-[3-(2-Pyridyl)propyl]-3-(propylcarbamoyl)guanidinedihydrochloride hydrate

20 g of corn starch

14 g of calcium carbonate, and

1 g of magnesium stearate.

The active compound and starch are thoroughly mixed, moistened with a 10percent gelatin solution, and granulated by pressing through a No. 20sieve. The granules are dried, thoroughly mixed with calcium carbonateand magnesium stearate, and compressed into tablets, each weighing about125 mg and containing 100 mg. The tablets are suitable foradministration to humans and small animals.

EXAMPLE XIII

Composition:

75 g of 1-(Propylcarbamoyl)-3-(2-pyridylmethyl)guanidine dihydrochloride

50 g of microcrystalline cellulose,

10 g of polyvinylpyrrolidine,

5 g of magnesium stearate, and

85 g of starch.

The active compound and cellulose are intimately mixed, moistened with apolyvinylpyrrolidine solution in water, and granulated by pressingthrough a No. 10 sieve. The dried granules are mixed with starch andmagnesium stearate and are compressed to dragee cores, each weighing 225mg. The cores are now provided with an elastic subcoat of an aqueoussugar solution containing 60 g of powdered acacia, 60 g of powderedgelatin, and 600 g of sugar per liter of solution. Thereafter a dustingpowder mixture of 180 g of powdered sugar, 60 g of powdered starch, 1 gof powdered talc, and 1 g of powdered acacia is applied to the drageecores. Coating with the gelatin subcoat and dusting are repeated abovefive times. The thus treated cores are sugar coated in the coating panwith a 60 percent sugar solution. Sugar coating is repeated until eachdragee weighs about 400 mg. The preparation is suitable foradministration to humans and small animals.

EXAMPLE XIV

This example illustrates the utilization of a representative member ofthe compounds of the present invention as an antimalarial agent in ananimal feed. In a manner similar to that described below, the remainingcompounds encompassed by the present invention may also be incorporatedas active antimalarial agents into animal feeds.

A medicated poultry feed intended as a starter feed for boilers isprepared by blending 0.005 percent by weight of1-(2,6-dimethylphenylcarbamoyl)-3-(2-pyridylmethyl)guanidine in a basicpoultry ration consisting of:

    ______________________________________                                        Ingredient                 Amount                                             ______________________________________                                        Corn meal, No. 2 yellow, ground, gms                                                                     1123                                               Stabilized grease or vegetable oil, gms                                                                  60                                                 Soybean oil meal (low fiber content 50%                                                                  480                                                protein) gms                                                                  Corn Gluten meal, gms      50                                                 Fish meal, antioxidant treated, 60% protein, gms                                                         30                                                 Fish solubles, dried basis, gms                                                                          10                                                 Meat and bone scraps, 50% protein, gms                                                                   140                                                Corn distillers dried solubles, gms                                                                      50                                                 Alfalfa meal, 17% protein 100,000 A/lb.                                                                  30                                                 Salt iodized, gms          5                                                  Manganese sulfate, feed grade, gm                                                                        0.75                                               Zinc carbonate or oxide, gm                                                                              0.25                                               Riboflavin, gms            3                                                  Vitamin B.sub.12, mgs      6                                                  Calcium pantotheante, gms  5                                                  Niacin, gms                30                                                 Stabilized vitamin A USP units                                                                           6,000,000                                          Vitamin D.sub.3, IC units  650,000                                            Vitamin E acetate, IU      5,000                                              Vitamin E (menadione sodium bisulfite) gms                                                               2                                                  DL-methionine or hydroxy analog, lb.                                                                     1                                                  Antioxidant (ethoxyquin or butylated                                                                     0.25                                               hydroxy toluene), lb.                                                         ______________________________________                                    

Similar feeds can be prepared containing any of the active amidinoureacompounds of Formula I.

EXAMPLE XV

Encapsulates of 1-Carbamoyl-3-(4-pyridylmethyl)guanidine dihydrochlorideare prepared by the procedure of U.S. Pat. No. 3,773,919 as follows:poly-L-lactide 10.0 g and 1.0 g 1-Carbamoyl-3-(4-pyridylmethyl)guanidinedihydrochloride were mixed and warmed to the melting point of thelactide. The mixture was cooled and ground into powder.

EXAMPLE XVI

Encapsulates of 1-[3-(2-Pyridyl)propyl]-3-(propylcarbamoyl)guanidinedihydrochloride hydrate are prepared following the procedure of U.S.Pat. No. 3,523,906 as follows: 5 g of the polycarbonate of2,2-bis(4-hydroxyphenyl)-propane are dissolved in 50 cc of methylenechloride to prepare a solution. In this solution is dispersed 1 g ofsalimomycin. This solution is emulsified to fine droplets in 150 ml ofethylene gylcol and the methylene chloride gradually evaporated. Thesolid microcapsules are collected by centrifuge and rinsed with water.

As stated hereinabove, the implants in the form of encapsulates releasethe amidinourea compound in an amount such that the blood contains 10-20nanogram %. As shown in the Examples, various types of encapsulates maybe used, all of which may have varying rates of release of the compoundand, when taken with the variation in sizes of animals, it can bereadily realized that varying sizes of implants, will be requireddepending on the situation. In general, however, the size of the implantwill vary from about 0.5 to about 4 grams and, if necessary, multipledosage forms may be administered to large animals such as cattle. Theamount of amidinourea in the implant may vary from about 5 to 95 wt.%.Encapsulates may be inserted through a slit in the skin or in the caseof microcapsules, administered by injection equipment.

We claim:
 1. A method for the treatment of protozoal infections inafflicted humans or animals which comprises administering thereto aneffective amount of a compound of the formula ##STR253## wherein: X is Oor S;n is 0 to 3; R₁ is a 5, 6 or 7 atom ring including 1 to 3 heteroatoms of N, O or S, or 2-purine, 6-purine, 8-purine, 9-purine,2-quinoline, 3-quinoline, 4-quinoline, 5-quinoline, 6-quinoline,7-quinoline, 8-quinoline, 1-isoquinoline, 3-isoquinoline,4-isoquinoline, 5-isoquinoline, 6-isoquinoline, 7-isoquinoline,8-isoquinoline, or carbazole, which may be substituted by lower alkyl,lower alkenyl, phenyl, substituted phenyl, lower alkynyl, phenyl loweralkyl, substituted phenyl lower alkyl, halo, nitro, cyano, sulfonyl,hydroxyl, carboxyl, lower alkanoyl, lower alkoxy, phenyl lower alkoxy,substituted phenyl lower alkoxy, halo lower alkoxy, amido, amino, loweralkylacyloxy, alkylamino, lower alkoxyamino, phenylalkoxyamino orsubstituted phenylalkoxyamino; or the N- or S-oxides thereof; providedR₁ is not pyridyl when n is 0; R₂, R₃ and R₄ are hydrogen or loweralkyl; R₅ and R₆ are hydrogen, lower alkyl, cycloloweralkyl, loweralkenyl, lower alkoxy, phenyl, substituted phenyl, phenyl lower alkyl,substituted phenyl lower alkyl or R₅ and R₆ together with the nitrogento which they are attached form a 3 to 7 atom ring which includes 0 to 2additional hetero atoms of N, O or S; wherein substituted phenyl means aphenyl group substituted by halo, lower alkyl, halo loweralkyl, nitro,amino, loweralkanoylamino, hydroxyl, loweralkoxy, phenylloweralkoxy,loweralkylacyloxy, cyano, halo loweralkoxy or loweralkyl sulfonyl; or apharmaceutically acceptable salt thereof.
 2. A method according to claim1, wherein:X is O or S; n is 0, 1, 2 or 3; R₁ is a substituted orunsubstituted 5, 6 or 7 atom ring including 1 to 3 hetero atoms of N, Oor S; and N- and S-oxides thereof; provided R₁ is not pyridyl when n is0; R₂ is hydrogen or lower alkyl; R₅ and R₆ are hydrogen, lower alkyl,cycloloweralkyl, lower alkoxy, phenylloweralkyl or substituted phenylloweralkyl, or R₅ and R₆ together with the nitrogen to which they areattached form a 3 to 7 atom heterocycle; or a pharmaceuticallyacceptable salt thereof.
 3. A method according to claim 1 wherein R₁ isa heterocycle selected from the group consisting of 1-pyrrole,2-pyrrole, 3-pyrrole, 2-furan, 3-furan, 2-thiophene, 3-thiophene,2-tetrahydrothiophene, 3-tetrahydrothiophene, 1-imidazole, 2-imidazole,4-imidazole, 2-oxazole, 4-oxazole, 5-oxazole, 2-thiazole, 4-thiazole,5-thiazole, 1-pyrazole, 3-pyrazole, 4-pyrazole, 5-pyrazole,1-pyrrolidine, 2-pyrrolidine, 3-pyrrolidine, 1-(3-pyrroline),2-(3-pyrroline), 3-(3-pyrroline), 2-pyrimidine, 4-pyrimidine,5-pyrimidine, 6-pyrimidine, 2-purine, 6-purine, 8-purine, 9-purine,2-quinoline, 3-quinoline, 4-quinoline, 5-quinoline, 6-quinoline,7-quinoline, 8-quinoline, 1-isoquinoline, 3-isoquinoline,4-isoquinoline, 5-isoquinoline, 6-isoquinoline, 7-isoquinoline,8-isoquinoline, and carbazole; where said heterocycle may be mono-, di-,tri- or tetra-substituted by lower alkyl, lower alkenyl, phenyl,substituted phenyl, lower alkynyl, phenyl lower alkyl, substitutedphenyl lower alkyl, halo, nitro, cyano, sulfonyl, hydroxyl, carboxyl,lower alkanoyl, lower alkoxy, phenyl lower alkoxy, substituted phenyllower alkoxy, halo lower alkoxy, amido, amino, lower alkylacyloxy,alkylamino, lower alkoxyamino, phenylalkoxyamino or substitutedphenylalkoxyamino.
 4. An animal feed additive comprising an effectiveanti-protozoal amount of a compound defined in claim 3 and an ediblecarrier material.